Targeting EED as a key PRC2 complex mediator toward novel epigenetic therapeutics

Abstract

EED within the PRC2 complex is crucial for chromatin regulation particularly in tumor development, making its inhibition a promising epigenetic therapeutic strategy. Significant advancement in PRC2 inhibitor development has been achieved with an approved EZH2 inhibitor in the market and with others in the clinical trials. However, current EZH2 inhibitors are limited to specific blood cancers and encounter therapeutic resistance. EED stabilizes PRC2 complex and enhances its activity through unique allosteric mechanisms, thereby acting as both a scaffold protein and a recognizer of H3K27me3 making it an attractive drug target. This review provides an overview of epigenetic therapeutic strategies targeting EED, including allosteric inhibitors, PPI inhibitors, and PROTACs, together with brief discussions on the relevant challenges, opportunities, and future directions.

Keywords: EED; PRC2; PROTACs; cancer therapy; epigenetic therapeutics; protein–protein interaction modulators.

FIGURE 1

(a) The involvement of EED in PRC2 functions in cancers. (b) The involvement of EED in noncanonical PRC2 functions in cancers.

FIGURE 2

(a) EZH2 domain structures (top) and EED domain structures (bottom). (b) Top view of the EED WD40-repeat domain with an H3K27me3 peptide (H3K27me3 peptide is shown as a stick model and colored green; EED is colored yellow; pdb:6C23). (c) Bottom view of the EED WD40-repeat domain with an EZH2 peptide (EBD).

FIGURE 3

(a) Representative EED inhibitors binding to the H3K9Me3 binding pocket. (b) Representative EED inhibitors disrupting EED–EZH2 PPI. (c) Representative EED-targeted PROTACs.